his cannot be how the future of medicine was imagined
back in 1928, the year Scottish bacteriologist Alexander Fleming
peered into his petri dish and noticed a bacteria-free ring surrounding
a growth of mold spores. Fleming's discovery-penicillin-promised
to forever change the treatment of infectious disease. Those
pre-World War II scientists and futurists must have imagined
that today, at the brink of the millennium, many of the human
body's most potent killers would be wiped out, ushering in an
era of unprecedented health and prosperity.

That promise has fallen a bit short. While
penicillin and other antibiotics have revolutionized the treatment
of many diseases, we still live in a world of killer bacteria.
As many as 80,000 people die in the United States annually from
staph infections; an estimated 3.5 million die each year worldwide
from tuberculosis (TB); and pneumonia remains a serious health
complication in developed and underdeveloped areas alike.

Our mistake, of course, has been to underestimate
the resourcefulness of bacteria. Our attempts to eradicate harmful
varieties have led to an all-out guerrilla warfare. Bacteria's
strategy: keep changing, mutating, developing resistance to the
drugs we deploy against them. In time, our weapons are rendered
useless. Bacteria is winning the war.

"The problem of drug resistance threatens to reverse
all the successes we have worked so hard for," says Margaret
Fischl, M.D., professor of medicine and director of the AIDS
Clinical Research Unit at the School of Medicine. "Attack-ing
this problem could be the greatest challenge in medicine today."

n
the 1940s, when antibiotics first became commercially available,
few people could have foreseen our predicament. Penicillin was
truly a wonder drug. But like all good things, too much of it
can cause trouble. In 1987 the National Institutes of Health
concluded that the emergence of drug-resistant bacteria is directly
caused by the incorrect and excessive use of antibiotics.

The problems are many. Bacteria become resistant to drug therapy
when they mutate into varieties that are able to avoid or combat
antibiotics. Sometimes they do this by changing their molecular
structure; other times by attacking the antibiotic itself. Such
mutations are an evolutionary inevitability. But the rate of
mutation is directly related to the bacteria's exposure to the
antibiotic. The more the exposure, the quicker the rate of mutation.
We have accelerated that rate by overprescribing the drugs.

While health care workers have long been aware of the problem,
misuse and abuse of antibiotics persist. According to a 1997
study published in the Journal of the American Medical Association,
one in five antibiotic prescriptions in the United States-totaling
more than 12 million-were written for ailments that do not respond
to such drugs. For example, researchers found that physicians
were prescribing antibiotics for two-thirds of bronchitis sufferers
and more than half of common cold sufferers.

Of course physicians aren't the only culprits. Patients often
demand the drugs for colds, flu, and other viruses that are not
affected by antibiotics. Some patients, believing they can endlessly
ward off disease, obtain prescriptions for ongoing, prophylactic
antibiotic use. Many physicians give in to such demands rather
than argue with the patient.

Overreliance on antibiotics-even when properly prescribed-also
contributes to the drug resistance crisis. For example, Gwen
Wurm, M.D., an assistant professor of clinical pediatrics at
the University, says even though many childhood ear ailments
heal just as quickly without antibiotics, many physicians prescribe
drugs at the slightest onset of infection. The emergence of managed
care's cost-containment strategies may be exacerbating the problem.

"The cheapest and easiest thing to do is to write a prescription
for antibiotics and never see the patient again," says Wurm.
"The alternative is to explain about the infection, explain
why antibiotics aren't the best course of treatment, explain
what parents should look out for in their child, and then have
a follow-up visit in 48 hours."

ompounding
the problem is the seductive allure-and intensive marketing-of
ever-more powerful drug companies. Although infections, when
possible, should be treated with drugs that attack the harmful
bacteria only, many physicians opt for broad-spectrum antibiotics
that may kill many other varieties. The body's exposure to such
antibiotics increases the odds of producing resistant mutations.
Mark Multach, M.D., associate professor of medicine and chief
of general internal medicine at the University of Miami, says
everyone plays a key role, including the pharmaceutical companies
who must bear some of the blame. "Doctors are barraged with
information from drug manufacturers saying that their drug works
best in this situation or that situation," says Multach.
"But is it really true? Just because a drug works doesn't
necessarily mean it is the best choice for a given condition."

Not surprisingly, the spread of antibiotic-resistant bacteria
is reaching epidemic proportions. In the mid-1980s the rate of
penicillin-resistant streptococcal bacteria (a leading cause
of pneumonia) was less than one-half percent. Today the figure
is upwards of 30 percent. Drug-resistant TB also has skyrocketed.
Fischl, who often sees the disease as a complication in HIV patients,
was on the frontline of a deadly outbreak of multidrug resistant
TB in Miami-Dade County in the early 1990s. A similar outbreak
occurred in New York City. Fischl says the epidemics may have
been initiated by a low rate of drug therapy compliance by TB
patients. When patients interrupt a course of antibiotics, the
surviving bacteria return with a vengeance, often having rapidly
mutated to resist the therapy.

Clearly, the war on bacteria is not over. With the proper
use of antibiotics, through improved health care protocols, drug-resistant
strains will be fewer and less virulent. To begin with, Multach
suggests, physicians must be more vigilant about identifying
specific infections and prescribe specific antibiotics. "It
may require a bit of extra work and may be a bit more expensive,
but a doctor needs to find out exactly what an infection is and
then find out what really works best," says Multach. "These
fancy new drugs are usually not the way to go."

Wurm agrees. She encourages physicians to think twice before
prescribing any antibiotic. If necessary, patients who seem unduly
enamored of antibiotics should be educated on the alternatives.
"It's not clear that every infection needs an antibiotic,"
says Wurm. "The human body is set up to fight infections
so there's no reason to call in the cavalry until we suspect
we're losing the battle."

But once antibiotics are prescribed, patient compliance is
vital. Fischl, who helped mount a response to Miami's multidrug-resistant
TB outbreak, says everything possible must be done to ensure
that patients complete their course of treatment. In Miami-Dade,
she says, the most important weapon in the war against TB has
been Direct Observational Therapy or DOT. Through DOT programs,
health care workers are dispatched into the community-to private
homes and clinics-to administer and supervise drug therapies.
In many cases they simply observe a patient swallowing pills.

DOT is expensive, but so is the treatment of drug-resistant
infections. A recent study estimated the combined cost of treating
patients with drug resistance complications at $30 billion a
year in the United States alone. "There's no easy, quick
solution," says Multach. "But we really can't afford
to ignore the problem any longer."

The Ultimate Weapon: Prevention

t's an
increasingly common scenario. A patient is prescribed drugs for
a particular illness but they are taken so long that they lose
their effectiveness. Drug resistance has set in. The alternative?
Develop a vaccine to prevent an illness from ever occurring.

"It's always better to prevent than to treat," says
Gunter Kraus, Ph.D., assistant professor of microbiology and
immunology at the School of Medicine. "Both scientifically
and economically, it makes more sense to develop vaccines that
have the potential to eradicate a condition, than to develop
drugs that could amount to lifelong treatment."

Dr.
Kraus is leading a research team in developing an AIDS vaccine,
a study funded by the National Institutes of Health.

Another breakthrough in the fight against drug resistance
is the ability of these vaccines to apply to any organism-bacterial
or viral. Many patients have a misconception that, when a "bug"
sets in, they need antibiotics, despite their doctor's diagnosis
of a viral infection. Antibiotics, which only treat bacterial
infections, are often requested by adults who refuse to heed
their doctors' directives that the drugs are unnecessary. The
development of future vaccines that address viral conditions
may reduce antibiotic overuse. Annual flu vaccines have already
helped decrease the usage.

The vaccine development process used by Dr. Kraus differs
from the more commonly known process in which weakened cells
from a virus (live attenuated virus) are administered to stimulate
the immune system to fight off the virus if later encountered.

Instead, Dr. Kraus will use a viral DNA model that transforms
the patient's own cells to stimulate the immune system-as opposed
to introducing external stimulants. The immune system then sends
the body's natural disease-fighting cells, known as T-cells,
to respond.

DNA vaccines are more practical than attenuated viruses. "Room
temperatures can inactivate an attenuated virus, making refrigeration
necessary to get it to a vaccination site. DNA is stable, so
no cooling is required, which makes the cost factor a big advantage
for this particular application."

-Rebecca Morris Riordan

David Villano is a frequent contributor to
the University's alumni magazines. Photography by John Zillioux
and Peter Poulides/Tony Stone.